Zamble D B, Jacks T, Lippard S J
Department of Chemistry, Howard Hughes Medical Institute, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Proc Natl Acad Sci U S A. 1998 May 26;95(11):6163-8. doi: 10.1073/pnas.95.11.6163.
Testicular cancers respond favorably to chemotherapy with the platinum-containing drug cis-diamminedichloroplatinum(II) (cisplatin). One factor that could explain the efficacy of cisplatin is the low frequency of p53 mutations observed in this tumor type. The present study examines the p53-mediated responses in murine testicular teratocarcinoma cells exposed to the drug. Cisplatin treatment of teratocarcinoma cells with a wild-type p53 gene resulted in accumulation of the p53 protein through posttranscriptional mechanisms; induction of p53-target genes was also observed. Drug treatment resulted in rapid apoptosis in p53-wild-type cells but not in p53(-/-) teratocarcinoma cells. In the latter cells, cisplatin exposure caused prolonged cell cycle arrest accompanied by induction of the p21 gene. Clonogenic assays demonstrated that the p53 mutation did not confer resistance to cisplatin. These experiments suggest that cisplatin inhibits cellular proliferation of testicular teratocarcinoma cells by two possible mechanisms, p53-dependent apoptosis and p53-independent cell cycle arrest.
睾丸癌对含铂药物顺二氯二氨合铂（II）（顺铂）的化疗反应良好。一个可以解释顺铂疗效的因素是在这种肿瘤类型中观察到的p53突变频率较低。本研究检测了暴露于该药物的小鼠睾丸畸胎瘤细胞中p53介导的反应。用野生型p53基因对畸胎瘤细胞进行顺铂处理，通过转录后机制导致p53蛋白积累；还观察到p53靶基因的诱导。药物处理导致p53野生型细胞迅速凋亡，但在p53（-/-）畸胎瘤细胞中未出现凋亡。在后者细胞中，顺铂暴露导致细胞周期长时间停滞，并伴有p21基因的诱导。克隆形成试验表明，p53突变并未赋予对顺铂的抗性。这些实验表明，顺铂通过两种可能的机制抑制睾丸畸胎瘤细胞的细胞增殖，即p53依赖性凋亡和p53非依赖性细胞周期停滞。
